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At least 1,045 records · Page 58Linked to original sources
PubMed1996

Amiodarone-induced lymphocyte toxicity and mitochondrial function.

Amiodarone is one of the most effective antiarrhythmic drugs available. However, its use is often limited by potentially life-threatening toxicities, including hepatotoxicity and pulmonary toxicity. We have used human lymphocytes as a system in which to study amiodarone-induced cytotoxicity. Using a tetrazolium dye reduction assay, we observed amiodarone-induced cytotoxicity with a lethal dose (LD)50 of 10.0 +/- 31.1 microM (mean +/- SD, n = 5) with a cellular concentration of 2.2 +/- 0.2 million/ml and of 55.5 and 39.2 microM with cellular concentrations of 8.9 and 7.2 million/ml, respectively, after only 2.75 h of drug exposure. Damage to mitochondria, but not other organelles, was observed with electron microscopy at an amiodarone concentration of 7.3 microM. Alterations in ATP synthesis and lactate dehydrogenase (LDH) release from cells had concentration-response curves similar to those for cytotoxicity. However, we did not observe extracellular accumulation of adenine nucleotides. These results suggest that amiodarone may have a direct toxic effect on mitochondria, beginning at < 10 microM, with membrane-damaging effects at higher drug concentrations.

Adenosine↗
PubMedDate not supplied

The effects of the methylating agent 1,2-bis(methylsulfonyl)-1-methylhydrazine on morphology, DNA content and mitochondrial function of Trypanosoma brucei subspecies.

Repeated exposure of trypanosomes in vitro or in vivo to low concentrations of the methylating agent 1,2-bis(methylsulfonyl)-1-methylhydrazine induces a series of moderately synchronous morphological and biochemical changes. Cell division halts and the long-slender bloodstream forms transform to short-stumpy forms via larger intermediate-stage cells which contain approximately double the normal G2 content of DNA. In common with naturally occurring short-stumpy trypanosomes, drug-induced short-stumpy forms do not infect rodents and when transferred to Cunningham's medium, transform to and replicate as procyclics. Furthermore, these short-stumpy forms exhibit alpha-ketoglutarate supported motility and oxygen consumption, acquire the ability to reduce nitroblue tetrazolium (NADH diaphorase positivity) and appear to be in the G1 or G0 stage of the cell cycle based upon DNA content.

Animals↗
PubMed2006

Role of cholesterol in amyloid cascade: cholesterol-dependent modulation of tau phosphorylation and mitochondrial function.

Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the epsilon4 allele increasing and the epsilon2 allele decreasing the risk of developing AD. ApoE is the major apolipoprotein that modulates cholesterol transport in the central nervous system, cholesterol being an essential component of membranes for maintaining their structure and functions. Epidemiological studies have suggested a link between serum cholesterol levels and AD development and the potential therapeutic effectiveness of statins for AD; and furthermore, biological studies have shown that amyloid beta-protein (Abeta) secretion is modulated by cellular cholesterol level. However, other lines of evidence show controversial results. In addition to the role of cholesterol in Abeta generation, different interactions of cholesterol with Abeta and its role in AD pathogenesis have been shown, i.e. Abeta affects cholesterol dynamics in neurons, and altered cholesterol metabolism in turn leads to neurodegeneration with abnormally phosphorylated tau (tauopathy). In this review, the reciprocal interactions between cholesterol and Abeta, and the role of cholesterol in tauopathy are discussed. The isoform-specific involvement of apoE in this cascade, in which high-density lipoprotein-like particles are generated and supplied to neurons to maintain cholesterol homeostasis, is also discussed.

Alzheimer Disease↗
PubMed1988

Mitochondrial function in normal and genetically altered cells and tissues.

The impact upon oxidative metabolism of normal and pathological variations of oxidative capability is just beginning to be understood, based upon the few examples of human and animal subject survivals and the relatively few cell systems in which the impact of molecular pathologies on function has been studied. On the one hand, difficulties of isolation of systems containing altered oxidases are significant because of ineffective assembly or small amounts of surviving isoenzymes, and on the other hand, unexpected fragilities of the oxidase system may lead to low yields when subjected to the preparative stresses appropriate to the wild types. To circumvent these problems, this paper describes the application, in vivo, of noninvasive, nondestructive techniques to study the function of cytochrome oxidase and other components of the respiratory chain, particularly cytochromes b-c1 in human subjects on the one hand, and in isolated cells on the other, principally mutants of Saccharomyces cerevisiae in which the subunit content is varied. Two principal spectroscopic approaches are employed: optical and phosphorus magnetic resonance spectroscopy (P MRS). Optical spectroscopy of the near red region of the spectrum provides effective analysis of brain and muscle, as does the surface coil of space-resolved phosphorus magnetic resonance. Both techniques are applicable to suspensions of single cells such as yeast. The optical method yields essential information on oxygen delivery to tissues by hemoglobin and myoglobin and oxygen utilization by cytochrome oxidase. P MRS affords essential information on the efficiency of ATP generation and the extent to which oxidative metabolism meets the needs of cell function in terms of the ratio of phosphocreatine to inorganic phosphate (PCr/Pi). This in turn enables the calculation of the velocity of oxidative metabolism, V, in relation to its maximum capability, Vm, according to a Michaelis-Menten relationship that involves control not only by ADP (Pi/PCr) and Pi, but also by oxygen and substrate deliveries. Thus, an overview of the functionality of mitochondria in cells and tissues is uniquely provided by this combined approach and thereby deficiencies of components of the respiratory chain are quantified.

Adenosine Triphosphate↗
PubMed1985

Relationship between growth inhibition and mitochondrial function in petite-negative yeasts. II. Effects of central nervous system drugs upon pathogenic and non-pathogenic Candida species.

Six nervous system drugs which inhibited vegetative reproduction of S. cerevisiae arrested also mitotic division of C. utilis, C. albicans and C. tropicalis. Chlorpromazine and chlorpheniramine which proved to be the most effective, affected respiration and cytochrome biosynthesis. Electrophoretic bands with MW congruent to 100 K were faint in silver-stained electrophoregrams of proteins from cells grown in the presence of a sub-inhibitory concentration of chlorpromazine.

Amitriptyline↗
PubMed1986

Regulation of phosphoenolpyruvate carboxykinase and pyruvate kinase in Saccharomyces cerevisiae grown in the presence of glycolytic and gluconeogenic carbon sources and the role of mitochondrial function on gluconeogenesis.

Phosphoenolpyruvate carboxykinase (PEPCKase) and pyruvate kinase (PKase) were measured in Saccharomyces cerevisiae grown in the presence of glycolytic and gluconeogenic carbon sources. The PEPCKase activity was highest in ethanol-grown cells. However, high PEPCKase activity was also observed in cells grown in 1% glucose, especially as compared with the activity of sucrose-, maltose-, or galactose-grown cells. Activity was first detected after 12 h when glucose was exhausted from the growth medium. The PKase activity was very high in glucose-grown cells; considerable activity was also present in ethanol- and pyruvate-grown cells. The absolute requirement of respiration for gluconeogenesis was demonstrated by the absence or significantly low levels of PEPCKase and fructose-1,6-bisphosphatase activities observed in respiratory deficient mutants, as well as in wild-type S. cerevisiae cells grown in the presence of glucose and antimycin A or chloramphenicol. Obligate glycolytic and gluconeogenic enzymes were present simultaneously only in stationary phase cells, but not in exponential phase cells; hence futile cycling could not occur in log phase cells regardless of the presence of carbon source in the growth medium.

Gluconeogenesis↗